Residents in medically underserved areas of Washington, DC have express the concern that the high incidence of cancer in their community is due to contaminants in their food and water, including metals. Results from our laboratory and others show that environmentally relevant amounts of specific metals and metalloids, referred to as metalloestrogens, activate estrogen receptor-alpha (ER?) in vitro and in vivo through a high affinity interaction with the ligand binding domain (LBD) of the receptor. These metals and metalloids fall into two separate subclasses, bivalent cations and oxyanions. New results from our laboratory suggest that metalloestrogens also activate progesterone receptor-B (PR-B). The ability to activate ER?, and potentially PR-B suggests that environmental exposure to metals and metalloids with estrogen- and progestin-like activity may increase the risk of developing breast cancer. In response to the concerns of the community, this application will address the question whether exposure to metals and metalloids increases the risk of developing breast cancer by testing the hypothesis that higher lifetime environmental exposure to metals and metalloids with estrogen- and progesterone-like activity is associated with higher mammographic density in women during the menopausal transition and delays or reduces the involution of mammary gland and the decline in mammographic breast density during this period. Aim 1 will determine whether metals and metalloids mimic the effects of estrogens and progestin on mammary gland morphology, stem and progenitor cells, and gene expression in a menopausal animal model (Aim 1a) and define the mechanisms by which metals and metalloids activate PR-B in in vitro assays (Aim 1b). Aim 2 will determine whether environmental exposure to metallohormones is associated with changes in breast density through the menopausal transition and define the mechanism by which metals and metalloids alter breast density. Specifically, Aim 2 will establish if: a, higher metallohormone levels are associated with increased mammographic density; b, higher metallohormone levels are associated with maintenance of higher breast density through the menopausal transition; and c, polymorphisms in the calcium pathway are associated with increased mammographic breast density indicating the mechanism through which bivalent cationic metallohormones increase risk. To accomplish these aims, we will continue to engage with our partners to get their input, to help collect data, and to translate and communicate the scientific findings to the community.